Mycobacterium tuberculosis (Mtb) infects approximately one third of the world's population. In the US, there are an estimated 10 to 15 million people infected with Mtb who have the potential to develop active disease. Among otherwise healthy persons, infection with Mtb is likely to be asymptomatic. In recent years it has become clear that if these individuals become immunosuppressed, as in cases of HIV infection, Mtb infection is reactivated. The purpose of this proposal is to use a murine model of pulmonary Mtb infection to dissect the host's immune response to identify factors that promote the formation and maintenance of granulomas during chronic Mtb infection and possible mechanisms that may also cause reactivation. Expression of anti-mycobacterial immunity depends on type 1 immune cytokines such as interferon-gamma that enable the host to mount a granulomatous inflammatory response to the infection. The lung provides an excellent environment for the organism to persist, despite the presence of a continuous immune response. Matrix metalloproteinases (MMPs) are endopeptidases that degrade the extracellular matrix and have been associated with various pathogenic states. Tissue inhibitors of MMPs regulate the activity of MMPs and provide a mechanism for controlling their activity. We propose that during pulmonary Mtb infection, MMPs are a dual-edged sword, being induced by Mtb, but required by the host to form the granuloma and then down regulated to maintain the structure. Specifically, increased MMP activity causes extracellular matrix degradation/tissue remodeling, which enables Mtb to disseminate and facilitates leukocyte trafficking into infected lungs, providing the foundation for granuloma formation. Finally, MMP down regulation is critical for fibrosis formation that is essential for granuloma stability. The MMPs that function during this process are macrophage-derived MMP-2, MMP-9 and MMP-12, which play significant roles in the disease process, being regulated directly by the virulent organism. Understanding how the immune response modulates MMP activity and produces tight, well-formed granulomas will provide insight into mechanisms that could accelerate and stabilize the natural healing process. It is intended that the information obtained from these investigations will provide a better understanding of the immunopathogenesis of tuberculosis and therefore allow for the development of better treatment regimens particularly during reactivation of infection that can be used in association with conventional anti-tuberculosis therapies. [unreadable] [unreadable] [unreadable]